The mechanism of leukocyte activation by chemotactic factors has been studied using electrophysiology, fluorescent probe, surface charge and ultrastructural techniques. Studies assessing the mechanism of modulating leukocyte locomotion indicate that limited secretion of specific granules, which accompanies chemotaxis, is associated with increased cell adhesiveness and increased availability of chemoattractant receptors. Vigorous exocytosis is associated with depressed chemotaxis, decreased availability of chemoattractant receptors, chemoattractant hydrolysis by secreted products and markedly increased cell adherence and aggregation. Human pyrogen has been shown to be a potent stimulator of neutrophil exocytosis and activation of the hexose monophosphate shunt. Studies of the two populations of neutrophils we had identified previously indicate that during the neutropenia that follows in vivo endotoxin or hemodialysis, a subpopulation of neutrophils with poorly demonstrable Fc receptors is the predominant neutrophil left in the circulation. Clinical studies assessing the effect of pharmacologic agents on the neutrophil subpopulations in normal subjects, patients with recurrent infection and host defense defects are underway.